In the WO 01/96338 A1 compounds of the general formula I
are described, wherein R11, R2, R4, R5 and Q are as defined therein. These compounds and their pharmaceutically acceptable salts are effective inhibitors of wild type HIV reverse transcriptase as well as inhibitors of several mutant strains. Due to their HIV-1 inhibitory activity these compounds are useful in the treatment of AIDS, ARC and related disorders associated with HIV-1 infection.
Several compounds according to the formula I wherein Q is a 1-oxido-4-quinolinyl- or 1-oxido-5-quinolinyl-group are disclosed in the WO 01/96338 A1. Their synthesis is depicted in the scheme 5 wherein a hydroxyquinoline is added to a 5,11-dihydro-8-(2-hydroxyethyl)-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one derivative in the presence of diisopropyl azodicarboxylate (DIAD) and Ph3P in THF (see example IX, step g)).
Furthermore in the WO 04/02989 a process and novel intermediates for making HIV reverse transcriptase inhibitors of the above formula I are described. The process involves the reaction of a halogene substituted 5,11-dihydro-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one with a malonate or malonate surrogate, the hydrolysis of the intermediate to yield a carboxylic acid or ester and the reduction of the carboxylic acid or ester group to yield a hydroxymethyl group. In a final step a quinolinol or oxyquinolinol is condensed.
M. E. Brik (Tetrahedron Letters Vol. 36, No. 31, 1995, pp. 5519–5522) describes the oxidation of secondary amines to nitroxides with OXONE® (trademark E.I. du Pont de Nemours) in an aqueous buffered solution. The active ingredient of OXONE® is peroxomonosulfate as annotated (see footnote 19). The phase-transfer reaction reported therein was carried out at 0° C. using a slight excess of OXONE® for the oxidative transformation. The acetone-catalyzed oxidation by peroxomonosulfate (OXONE®) was performed in CH2Cl2/buffered water (pH 7.5–8), biphasic system and Bu4NHSO4 as a phase-transfer catalyst. The process involves the formation of dimethyloxirane by nucleophilic attack of the peroxomonosulfate on the carbonyl carbon with subsequent loss of potassium hydrogen sulfate. The oxygen is transfered to the secondary amine in a biphasic medium affording the oxidized product (nitroxide) and regenerating the initial ketone. As secondary amines derivatives of 2,5-dihydropyrrole, pyrrolidine, oxazolidine, diphenylamine, 10,11-dihydro-5H-dibenzo[b,f]azepine were transformed to the respective nitroxide products.